The present invention relates to dermal augmentation and tissue bulking, particularly for the treatment of gastroesophageal reflux disease, urinary incontinence, urinary reflux disease, or skin contour deficiencies and wrinkles, using injectable microspheres.
Although gastroesophageal reflux is a normal physiological phenomenon, in some cases it is a pathophysiological situation that can result in a variety of symptoms which may become severe in extreme cases. Gasiro-Esophageal Reflux Disease (xe2x80x9cGERDxe2x80x9d), describes a backflow of acidic and enzymatic liquid from the stomach to the esophagus. It causes burning sensations behind the sternum that may be accompanied by regurgitation of gastric acid into the mouth or even the lung. Complications of GERD which define the severity of the disease include esophageal tissue erosion, and esophageal ulcer wherein normal epithelium is replaced by a pathological tissue.
Statistical data indicate that about 35% of the American population suffer from heartburn at least once a month and between 5 to 10% once a day. More importantly for this kind of disease about 2% of the American population suffer from GERD based on medical evidence data from endoscopic examination. This disease is related to the age of individuals and seems to increase after 40 years of age. (Nebel O. T. et al., Am. J. Dig. Dis., 21(11):953-956 (1976 )).
In normal patients, after a meal the lower esophageal sphincter remains closed, but in patients with GERD, it relaxes and allows some acidic material to reflux into the esophageal tube as a result of stomach contractions. Actually GERD can be attributed primarily to transient relaxation of the lower esophageal sphincter. In other cases, GERD can be attributed to decreased resting tone of the lower esophageal sphincter or to congenital small dimension of the sphincter itself. Other causes also exist which contribute to varying degrees to the existence and severity of this disease.
In addition, there are external factors that contribute to exacerbate the symptoms of GERD, which conditions include eating fatty foods, caffeine intake, smoking, tight clothing and certain medications. Decrease in salivation can also be a factor that exacerbates GERD, since under normal conditions saliva, which is an alkaline liquid, aids in neutralizing acidic reflux and therefore diminishing the duration of the acidic exposure of the esophagus.
Erythema is one of the first visible signs of GERD, which can be seen by endoscopy. Tissue erosion indicates more advanced disease which can then become deep ulcers and lead to cancer (adenocarcinoma increases in incidence faster than other types of cancer). Diffuse ulceration and specific complications occur in about 3.5% of patients less than 65 years of age with esophageal obstruction, blood loss, and in some cases, perforation. Ulcerative situations not only lead to complications, but they are also more resistant to treatments. Although severe complications are uncommon in young patients, they occur in about 20-30% of patients over 65 (Reynolds J. C, Am. J. Health-Sys. Pharm 53, (1996)).
Prior to the present invention, in an attempt to increase the function of the sphincter, bulking methods using bovine collagen and Teflon paste have been used in patients. Both methods have been unsuccessful, however, as these materials migrate over time from the initial site of implantation.
At present, GERD is generally managed by over-the-counter (xe2x80x9cOTCxe2x80x9d) antacids or prescription drugs, including proton pump inhibitors, motility agents and H2 blockers. In addition, a portion of GERD patients require surgical intervention; the most common type of surgery is fundoplication which can be done by conventional surgical techniques, or using laparoscopic techniques. However, fundoplication surgery carries the risk of serious side effects and is only marginally successful in curing GERD. Respiratory symptoms are also associated with GERD in about 50% of patients, and in patients undergoing fundoplication, these respiratory symptoms can even increase (76% reported in a study by Johnson W. E. et al., Archives of Surgery, 131:489-492 (1996)).
Urinary incontinence is a prevalent problem that affects people of all ages and levels of physical health, both in the community at large and in healthcare settings. Medically, urinary incontinence predisposes a patient to urinary tract infections, pressure ulcers, perineal rashes, and urosepsis. Socially and psychologically, urinary incontinence is associated with embarrassment, social stigmatization, depression, and especially for the elderly, an increased risk of institutionalization (Herzo et al., Ann. Rev. Gerontol. Geriatrics, 9:74 (1989)). Economically, the costs are astounding; in the United States alone, over ten billion dollars per year is spent managing incontinence.
Incontinence can be attributed to genuine urinary stress (urethra hypermobility), to intrinsic sphincter deficiency (xe2x80x9cISDxe2x80x9d), or both. It is especially prevalent in women, and to a lesser extent incontinence is present in children (in particular, ISD), and in men following radical prostatectomy.
One approach for treatment of urinary incontinence involves administration of drugs with bladder relaxant properties, with anticholinergic medications representing the mainstay of such drugs. For example, anticholinergics such as propantheline bromide, and combination smooth muscle relaxant/anticholinergics such as racemic oxybutynin and dicyclomin, have been used to treat urge incontinence. (See, e.g., A. J. Wein, Urol. Clin. N. Am., 22:557 (1995)). Often, however, such drug therapies do not achieve complete success with all classes of incontinent patients, and often results in the patient experiencing significant side effects.
Besides drug therapies, other options used by the skilled artisan prior to the present invention include the use of artificial sphincters (Lima S. V. C. et al., J. Urology, 156:622-624 (1996), Levesque P. E. et al., J. Urology, 156:625-628 (1996)), bladder neck support prosthesis (Kondo A. et al., J. Urology, 157:824-827 (1996)), injection of crosslinked collagen (Berman C. J. etal., J. Urology, 157:122-124 (1997), Perez L. M. etal., J. Urology, 156:633-636 (1996); Leonard M. P. et al., J. Urology, 156:637-640 (1996)), and injection of polytetrafluoroethylene (Perez L. M. et al., J. Urology, 156:633-636 (1996)).
A recent well known approach for the treatment of urinary incontinence associated with ISD is to subject the patient to periurethral endoscopic collagen injections. This augments the bladder muscle in an effort to reduce the likelihood of bladder leakage or stress incontinence.
Existing solutions to circumvent incontinence have well known drawbacks. The use of artificial sphincters for children with intractable incontinence requires long term surveillance of the urinary tract because of the potential for renal failure after device placement (Levesque P. E. et al., J. Urology, 156:625-628 (1996)). While endoscopically directed injections of collagen around the bladder neck has a quite high success rate in sphincter deficiency with no significant morbidity, the use of collagen can result in failures that occur after an average of two years and considerations need to be given to its cost effectiveness (Khullar V. et al., British J. Obstetrics and Gynecology, 104:96-99 (1996)). In addition, deterioration of patient continency, probably due to the migration phenomena (Perez L. M. et al.) may require repeated injections in order to restore continency (Herschorn S. et al., J. Urology, 156:1305-1309 (1996)).
The results with using collagen following radical prostatectomy for the treatment of stress urinary incontinence have also been generally disappointing (Klutke C. G. et al., J. Urology, 156:1703-1706 (1996)). Moreover, one study provides evidence that the injection of bovine dermal collagen produced specific antibodies of IgG and IgA class. (McCell and, M. and Delustro, F., J. Urology 155, 2068-2073 (1996)). Thus, possible patient sensitization to the collagen could be expected over the time.
Despite of the limited success rate, transurethral collagen injection therapy remains an acceptable treatment for intrinsic sphincter deficiency, due to the lack other suitable alternatives.
Urinary reflux disease, or xe2x80x9cvesicoureteral refluxxe2x80x9d in its medical term, simply means that urine goes backwards in the ureters during urination. The disease often occurs in young children. The ureter is the tube which connects the kidneys with the bladder. Urine is supposed to go in one direction: from the kidneys to the bladder. When urine goes up from the bladder to the kidneys, it can result in health problems for the person.
Urinary reflux can lead to kidney damage. Refluxing urine can carry bacteria to the kidney, where it can cause kidney infection. Children with reflux of urine are much more likely to have kidney infection than children who do not have reflux. The combination of reflux and infection can lead to areas of permanent kidney damage or xe2x80x9crenal scarring.xe2x80x9d This scarring is detected by doing an X-ray called an intravenous pyelogram (IVP), or preferably, a renal scan. If it is extensive enough, the scarring can lead to loss of function of one or both kidneys.
The key to preventing renal scarring is preventing kidney infections. This is currently being carried out in two ways. In most cases, long term prophylactic antibiotics are given. The other method of preventing urinary tract infections is surgical correction of the reflux. Both methods, however, have drawbacks. Long term use of antibiotics may cause unpredictable side effects and surgical procedures involve unnecessary risks.
Even though many urinary reflux disease will go away on its own in children, some cases often lead to severe kidney and urinary tract infections and even total kidney failure. There is a need, therefore, for a safe, effective, less intrusive, and long lasting method of treating urinary reflux disease.
Damage to the skin due to aging, environmental exposure to the sun and other elements, weight loss, child bearing, disease such as acne and cancer, and surgery often results in skin contour deficiencies and other skin anomalies. In order to correct contour deficiencies and other anomalies of the skin, people often resort to cosmetic surgery, such as face lifts and skin tucks. Cosmetic surgery, however, has several drawbacks, in addition to the high cost associated with it. It is usually an invasive and risky procedure, having the potential of leaving scars in areas of operation and affecting normal biological and physiological functions. Furthermore, cosmetic surgery is often a limited option, available only for certain skin deficiencies.
In addition to cosmetic surgery, various other methods are used to remove or ameliorate the deficiencies with different levels of success. The use of injectable material for soft tissue augmentation is a method often used. The advantage of using hypodermic needles as a delivery device for dermal augmentation reflects the advantages of using hypodermic needles in general: easy, precise and, usually, non-invasive deliveries. Yet, the requirement for such use is also quite strict: the material to be delivered must be deliverable through the needles, which means the material must be able to easily pass through the hollow centers of the needles.
One method of dermal augmentation using injectable material is liquid or semiliquid liquid injections, usually containing collagen. The best known example is a collagen preparation manufactured by Collagen Corporation (now part of Inamed Corporation) and marketed by C. R. Bard. However, collagen is a naturally occurring substance which the body may enzymatically degrade and eliminate over time, thus requiring repeat treatments. Also, collagen may be displaced within the tissue in which it was originally injected, thereby reducing or eliminating the intended dermal augmentation effect. Collagen is also digested directly (biochemically), through macrophages, through the lymphatic system, or by other means. Even more alarming from a cosmetic perspective, collagen may move from the initial site of injection, causing unsightly bumps and bulges under the skin at undesired locations. See, e.g., Millikan, Long Term Safety and Efficacy with Fibrel in the Treatment of Cutaneous Scars, J Dermatol Surg Oncol, 15:837-846 (1989).
Injection of liquid silicone has also been used extensively to treat skin deficiencies. However, due to long term side effects, such as nodules, recurring cellulitis, and skin ulcers, the use of injectable silicone is on the decline. See, e.g., Edgerton et al., Indications for and pitfalls of soft tissue augmentation with liquid silicone, Plast. Reconstr. Surg, 58:157-163 (1976).
Prior to the present invention, microspheres have been manufactured and marketed for in vitro use in anchorage dependent cell culture. (Van Vezel, A. L., Nature, 216:64-65 (1967); Levine et al., Somatic Cell Genetics, 3:149-155 (1977); Obrenovitch et al., Biol. Cell., 46:249-256 (1983)). They have also been used in vivo to occlude blood vessels in the treatment of arteriovascular malformation, fistulas and tumors (See, U.S. Pat. No. 5,635,215, issued Jun. 3, 1997 to Boschetti et al.; Laurent et al., J Am. Soc. Neuroiol, 17:533-540 (1996); and Beaujeux et al. J. Am. Soc. Neuroial, A:533-540 (1996)).
Further, direct implantation of cells into living tissues such as brain or liver to correct specific deficiencies has been attempted albeit with a number of failures. The major problems associated with direct cell transplantation are the long term viability of the cell transplant and the immunopathological as well as histological responses. Microparticles with cells attached on their surface have been used in some in vivo applications. Cherkesey et al., IBRO, 657-664 (1996), described the culture of adrenal cells on coated dextran beads and the implantation into mammalian brain to supplant some specific disorders related to 6-hydroxydopamine-induced unilateral lesions of the substantia nigra. The pre-attachment of cells to dextran microcarriers allowed for improved functions of the cells implanted into the brain. Also liver cells transplantation has been used to manage acute liver failure, or for the replacement of specific deficient functions such as conjugation of bilirubin or synthesis of albumin. For this purpose, an intrasplenic injection of hepatocytes grown on the surface of microspheres was performed (Roy Chowdhury et al., in: Advanced Research on Animal Cell Technology, AOA Miller ed., 315-327, Kluers Acad. Press, 1989).
Most of cell implant results have been, however, largely disappointing for the designated functions (or have had low levels of biological function).
Prior to the present invention, solid microparticles have also been used for the correction of skin deficiencies and for tissue bulking. For example, carbon particles, silicone particles, TEFLON paste, collagen beads and polymethylmethacrylate spheres, have been used with disappointing results due to, inter alia, adverse tissue reactions, biological degradation and migration from the initial implantation location.
The problems associated with rigid and non-deformable particles, such as carbon particles and silicone particles, in tissue bulking or treating skin deficiencies are that they are either too fragile or too large to be injected, or too small and are digested or eliminated by the body. Therefore, such particles all have one or more of the following limitations: (i) too large to be injected through a 30 gauge or smaller needle; (ii) particles of irregular shape clump together, making injection difficult; (iii) particles are too fragile, resulting in breakage during injection and digestion of the residues; (iv) injected particles are too small and are digested by macrophages or other components of the lymphatic system; and (v) injected particles are displaced as they do not adhere to the surrounding cells.
Injectable deformable particles, such as Teflon(copyright) particles, have also been used for tissue bulking and for treating skin deficiencies. However, Teflon(copyright) particles have one or more of the following limitations: (1) the particles slide with the tissue and do not stay in place of injection; (2) the particles deform during and after injection, reducing the intended tissue bulking effect; and (3) the particles are digested or eliminated by the lymphatic system partly due to the fact that their diameters become smaller as a result of injection.
Therefore, there is a great need for safe, biocompatible, stable and effective methods of tissue bulking for the treatment of GERD, urinary incontinence, and urinary reflux disease and methods of dermal augmentation for treatment of skin disorders.
The present invention encompasses the use of implantable microparticles, or microspheres or microbeads, in the treatment of GERD, urinary incontinence, urinary reflux disease and skin deficiencies such as skin wrinkles. In each use the particles are implanted into the appropriate tissue, muscle, organ etc. as a bulking or augmentation agent.
In a preferred embodiment, the invention provides a method of dermal augmentation, suitable for the treatment of skin deficiencies, and a method of tissue bulking, suitable for the treatment of GERD, urinary incontinence, or urinary reflux disease, wherein the microspheres used are injectable through needles of about 18 gauge or smaller, depending on the particular method and treatment, and are not capable of being digested or eliminated through the lymphatic or the immune system. Thus, the invention encompasses injectable compositions and methods for dermal augmentation or tissue bulking by injecting using syringes, catheters, needles or other means of injecting or infusing microspheres in a liquid medium so as to avoid surgical intervention.
The microparticles of the invention, whether implantable by injection or otherwise, are preferably pre-coated, with autologous cells, for example, muscle cells, fat cells and the like. The microparticles of the invention are biocompatible non-toxic polymers coated with, linked to or filled with cell adhesion promoters. The microparticles preferably contain a positive charge on their surface by way of a cationic monomer or polymer.
In one embodiment, the invention encompasses the treatment of gastroesophageal reflux disease in a human which comprises implanting hydrophilic biocompatible microparticles comprising (a) a positive charge and a cell adhesion promoter; and (b) autologous cells layered on the surface of said beads, into the lower esophageal sphincter.
The microparticles are preferably microspheres or microbeads which are described in detail herein. The autologous cells are preferably taken from the area where the implantation is to be made. Serum or whole blood taken from the patient can be used to wash the microparticles prior to implantation. For GERD treatment, implantation is preferably made by using standard techniques known to the ordinary skilled artisan, such as injection (or injections) via syringe or other suitable devices.
In yet another embodiment, the invention encompasses the treatment of urinary incontinence in a human which comprises implanting hydrophilic biocompatible microparticles comprising (a) a positive charge and a cell adhesion promoter; and (b) autologous cells layered on the surface of the beads, into the urinary sphincter. The microparticles are preferably microspheres or microbeads as described herein. Further, the autologous cells are preferably taken from the area where the implantation is to be made. Serum or whole blood from the patient can be used to wash the microparticles prior to implantation. Implantation is preferably made using a syringe or other device suitable for the particular tissue of implantation.
In another embodiment, the invention encompasses a method of treating skin wrinkles in a human which comprises the administration or implantation of microparticles comprising a hydrophilic copolymer having a positive charge, and a cell adhesion promoter, which microparticles have been pre-treated with autologous cells. The microparticles can be simply exposed to the autologous cells or mixed thoroughly with autologous cells prior to implantation. The microspheres are preferably injected via syringe or other suitable device through a needle of 30 gauge or smaller into the area, or under the area, of the skin deficiencies.
In yet another embodiment, the invention encompasses the treatment or amelioration of skin wrinkles which comprises administering hydrophilic biocompatible microparticles comprising: (a) a positive charge and a cell adhesion promoter; and (b) autologous cells, collagen, collagen derivatives or glucosaminoglycans layered on the surface of the beads, into the area of or surrounding the skin wrinkles. In other words, microspheres or microbeads coated with a cell adhesion promoter and pre-treated with the appropriate tissue bulking cells, are administered to the area of treatment.
The present invention additionally provides methods of dermal augmentation and treatment of skin deficiency. Specifically, the invention provides a method of causing dermal augmentation in a mammal by administering a composition of elastic, hydrophilic, and substantially spherical microspheres in a biocompatible carrier to the mammal. The composition is injectable through a needle of about 30 guage or smaller and the microspheres are not capable of being digested or eliminated by macrophage or other elements of the mammal""s immune system. According to the present invention, a preferred method-of administration is injecting the composition into an area of the subject mammal that is in need of dermal augmentation. A more preferred method of administration is injecting the composition into the subcutaneous layer of the subject mammal.
The dermal augmentation method of the present invention is especially suitable for the treatment of skin contour deficiencies, which are often caused by aging, environmental exposure, weight loss, child bearing, injury, surgery, in addition to diseases such as acne and cancer. Suitable for the treatment by the present invention""s method are contour deficiencies such as frown lines, worry lines, wrinkles, crow""s feet, marionette lines, stretch marks, and internal or external scars resulted from injury, wound, bite, surgery, or accident.
The invention also encompasses the use of the injectable compositions to treat skin deficiencies caused by diseases such as acne and cancer.
The present invention further provides a method of causing dermal augmentation in a mammal by administering the injectable suspension extracorporeally into organs, components of organs, or tissues prior to the inclusion of said tissues, organs, or components of organs into the body.
The invention further encompasses method for tissue bulking in a mammal by administering a composition of elastic, hydrophilic, non-toxic and substantially spherical microspheres in a biocompatible carrier to the mammal. The composition is injectable through needles of about 18 to about 26 gauge, preferably, 22 to 24 gauge, and preferably administered by injection directly into the site of treatment, e.g., the sphincter.
Thus, in one embodiment, the tissue bulking method is used for the treatment of gastroesophageal reflux disease in a mammal; preferably by direct administration via injection of the composition into the lower esophageal sphincter or the diaphragm of the mammal.
Similarly, the tissue bulking method is used for the treatment of urinary incontinence or urinary reflux disease via administration of the composition into the bladder sphincter or the urethra of the mammal.
The present invention further provides kit for performing dermal augmentation or tissue bulking. The kit comprises a syringe and a 30 guage or smaller needle for dermal augmentation and an 18 to 26 gauge needle for tissue bulking. The syringe optionally comprises a composition of elastic, hydrophilic, non-toxic and substantially spherical microspheres in a biocompatible carrier. Alternatively, the syringe does not contain a solution or suspension but is accompanied by (a) dry sterilized microspheres which are ready for preparation of a suspension; (b) a preformed suspension of microspheres; and (c) dry microspheres and a biocompatible solution in separate containers. The final composition of microspheres is injectable through the needle into a mammal and the microspheres are not capable of being digested or eliminated through said mammal""s macrophages or other elements of the immune system or the lymphatic system.
It should be recognized that both treatments for GERD, urinary incontinence, urinary reflux disease, and skin deficiencies described above can be used in combination with conventional therapies now used to treat these diseases or conditions i.e., oral diuretics, antacids, suitable drug therapy, cometic surgeries and the like. Such combination therapy can lead to a faster, safer and more comfortable recovery for the patient.
As used herein the terms xe2x80x9cadministeredxe2x80x9d, xe2x80x9cimplantedxe2x80x9d, or xe2x80x9cimplantationxe2x80x9d are used interchangeably and mean that the material is delivered to the area of treatment by techniques know to those skilled in the art and appropriate for the disease to be treated. Both invasive and non-invasive methods may be used for delivery. xe2x80x9cInjectablexe2x80x9d as used in the present invention means capable of being administered, delivered or carried into the body via needle or other similar ways.
As used in the present invention, xe2x80x9cmicroparticlesxe2x80x9d means polymer or combinations of polymers made into bodies of various sizes. The microparticles can be in any shape, although they are often in substantially spherical shape, in which case the microparticles are referred to as xe2x80x9cmicrospheresxe2x80x9d or xe2x80x9cmicrobeads.xe2x80x9d Before injection or being composed into an injectable composition, the microspheres are sterilized. xe2x80x9cElasticxe2x80x9d microparticles or microspheres refers to microparticles or microspheres comprise polymers that have elastic properties. Specific to the present invention, elastic microspheres means particles that are flexible enough so that they can be easily injected through needles of 18 gauge or smaller, yet the microspheres are not fragile so that they are not broken during the process of injection.
The microspheres of the present invention also comprise particles that are xe2x80x9chydrophilic,xe2x80x9d which, as used in the invention, means the particles can dissolve in, absorb, or mix easily with water or aqueous solution. xe2x80x9cSubstantially sphericalxe2x80x9d generally means a shape that is close to a perfect sphere, which is defined as a volume that presents the lowest external surface area. Specifically, xe2x80x9csubstantially sphericalxe2x80x9d in the present invention means, when viewing any cross-section of the particle, the difference between the average major diameter and the average minor diameter is less than 20%. The surfaces of the microspheres of the present invention appear smooth under magnification of up to 1000 times. The microspheres of the present invention may comprise, in addition to the particles, other materials as described and defined herein. xe2x80x9cSkin wrinkles,xe2x80x9d xe2x80x9cskin deficiencies,xe2x80x9d and xe2x80x9cskin contour deficienciesxe2x80x9d are used interchangeable in the present invention to refer to skin conditions that are either abnormal or undesirable due to various internal or external conditions such as aging, environmental exposure to the sun and other elements, weight loss, child bearing, disease such as acne and cancer, surgery, wounds, accidents, bites, cuts. xe2x80x9cDermal augmentationxe2x80x9d in the context of the present invention refers to any change of the natural state of a mammal""s skin and related areas due to external acts. The areas that may be changed by dermal augmentation include, but not limited to, epidermis, dermis, subcutaneous layer, fat, arrector pill muscle, hair shaft, sweat pore, and sebaceous gland. xe2x80x9cTissue bulkingxe2x80x9d in the context of the present invention refers to any change of the natural state of a mammal""s non-dermal soft tissues due to external acts or effects. The tissues encompassed by the invention include, but not limited to, muscle tissues, connective tissues, fats, and, nerve tissues. The tissues encompassed by the present invention may be part of many organs or body parts including, but not limited to, the sphincter, the bladder sphincter and urethra. xe2x80x9cCell adhesion promoterxe2x80x9d in the present invention means any material that, because of their presence in or association with the microspheres, promotes or enhances the adhesiveness of cells to the surface of the microspheres. These materials are often proteins that are bound to the surface of the microspheres through covalent bonds of the proteins and the polymers.
xe2x80x9cTherapeutic agentxe2x80x9d in the present invention refers to any substance that provides therapeutic effects or biological or physiological responses to the dermal augmentation or tissue bulking procedure. An example of therapeutic agent is an anti-inflammation agent that prevents or reduce the effect of inflammations associated dermal augmentation or tissue bulking procedure, an anti-inflammatory agent, an anti-bacterial agent, or an anti-histamine agent.
xe2x80x9cChemical modificationxe2x80x9d in the present invention means the changes of chemical properties and characteristics of the microspheres, either during their production process or by way of mixing or contacting them with various agents or tissues, such that the microspheres have the ability to perform, in addition to dermal augmentation or tissue bulking, other functions once injected into the body.